Clinically significant pains are produced by intense or prolonged nociceptor activity and/or nerve injury. These stimuli initiate physiological and, in some cases, anatomical changes in the peripheral and central nervous system that may amplify and prolong activity in nociceptive afferent pathways and increase pain perception. The unifying theme of this program project is the study of mechanisms that prolong or enhance pain perception following tissue or nerve injury. Several different approaches will be used. Dr. Ralston will examine the anatomical reorganization of the dorsal horn and ventrobasal thalamus following peripheral nerve injury. Dr. Rowbotham will study the contribution of activity in damaged primary afferent nociceptors and deafferentation to pain in patients with post herpetic neuralgia. Dr. Levine will study sympathetic nervous system influences on primary and secondary hyperalgesia induced by intradermal capsaicin. Dr. Basbaum will study the role in pain transmission of spinal neurons bearing the neurokinin one receptor and of primary afferent terminals that express the NMDA receptor and will use in vivo microdialysis to monitor the regulation of GABA in the RVM. Dr. Fields will study the connectivity and transmitter content of brainstem neurons that modulate spinal nociceptive transmission. A highly interactive and cohesive group effort will be fostered through a program of active collaboration, shared equipment and techniques and formal teaching and research conferences.